1. What to do when basal bolus therapy fails in Type 2 Diabetes [insert name] UKHMG00596a February 2012 Prescribing information can be found on the last slide

2. This meeting has been developed and sponsored by UKHMG00596a February 2012

3. Cerebrovascular event** UKPDS: A 1% decrease in HbA 1c is associated with a reduction in complications Deaths related to diabetes* Stratton IM et al (2000) BMJ 321: 405–12 Microvascular complications e.g. Renal disease and blindness* Amputation or fatal peripheral vascular disease* Myocardial infarction* *P<0.0001; ** P=0.035. UKPDS=United Kingdom Prospective Diabetes Study. HbA 1c 1% 37% 43% 21% 14% 12% UKHMG00596a February 2012

4. Beta-cell dysfunction – a core defect in type 2 diabetes Genetic and environmental pathophysiology One of the two core defects in type 2 diabetes Therapeutic strategies should ideally target both defects Del Prato S, Marchetti P (2004) Diabetes Technol Ther 6: 719–31 Insulin resistance Beta-cell dysfunction Type 2 diabetes + = Impaired ability to secrete insulin and compensate for insulin resistance UKHMG00596a February 2012

5. Insulin and glucose patterns: Basal vs. mealtime hyperglycaemia in type 2 diabetes Plasma glucose concentration (mmol/L) 10.0 5.0 0 06001200 Time of day (hours) 180000000600 7.5 12.5 2.5 15.0 Adapted from Riddle MC (1990) Diabetes Care 13: 676–86 UKHMG00596a February 2012 Diagram shows 24-hour plasma glycaemic pattern typical of healthy people (lower border of grey area) and those with mild non- insulin dependent diabetes mellitus (upper border of grey area). Red area shows part of the glycaemic abnormality of diabetes accounted for by excessive postprandial hyperglycaemia, whereas grey area shows part due to elevated basal glycaemia.

6. As people with diabetes get closer to HbA 1c targets, the need to manage postprandial glucose (PPG) increases 100 0 50 Relative contribution (%) >10.210.2―9.39.2―8.58.4―7.3 <7.3 HbA 1c (%) quintiles 70% 30% Fasting Plasma Glucose Postprandial Glucose Adapted from Monnier L et al (2003) Diabetes Care 26: 881–5 UKHMG00596a February 2012

7. There are several ways of addressing PPG and FPG with insulin Basal–bolus insulin therapy Premixed insulin therapy (with various ratios of longer- and shorter-acting insulin components) FPG=fasting plasma glucose; PPG=postprandial glucose. UKHMG00596a February 2012

8. In Non-diabetic Individuals, Basal Secretion Represents Approximately 50% Total Daily Insulin Normal Obese Polonsky KS et al. (1988) J Clin Invest; 81:442-48 0 100 200 300 400 500 600 Percent Basal Insulin Secretion 0600100014001800220002000600 Clock Time (hours) When the basal insulin secretion rate was extrapolated over a 24-h period and expressed as a percentage of the total 24-h insulin secretion, basal secretion represented 50.1±3.1% of the total 24-h insulin secretion in normal subjects and 45.2±2.2% in obese patients. UKHMG00596a February 2012

9. Basal Dose Bolus Dose % Total Daily Insulin Dose Multiple Daily Injection (n=50) Continuous Subcutaneous Insulin Infusion (n=48) Patients With Type 2 Diabetes on Intensive Insulin Therapy Regimens Use 50% Basal and 50% Bolus Insulin Doses adjusted to achieve target preprandial and bedtime BG levels Herman WH et al. (2005) Diabetes Care; 28:1568-73 After titrating doses throughout the study each group independently had a regimen that consisted of approx 50% basal and 50% preprandial insulin UKHMG00596a February 2012

10. Is basal–bolus always the gold standard? High injection frequency can lead to poor adherence, causing inadequate glycaemic control 1 Many people with type 2 diabetes on basal–bolus therapy have suboptimal glycaemic control. In one large study*, almost two thirds of people failed to achieve HbA 1c <7% (<53 mmol/mol) 2 1.Donnelly LA et al (2007) Q J Med 100: 345–50 2.Hollander P et al (2008) Clin Ther 30: 1976–87 *This was a multinational, 52-week, open-label, parallel-group, non-inferiority, treat-to-target trial, designed to compare the efficacy and safety profiles of detemir and glargine as the basal insulin component of a basal–bolus regimen in people with type 2 diabetes. Insulin aspart was used as the bolus insulin. The intention-to-treat population included 319 participants. UKHMG00596a February 2012

11. Currently available human and analogue premixed insulins Composition Human insulins Biphasic human insulin (Humulin ® M3)30% soluble insulin70% isophane insulin Biphasic human insulin (Insuman ® Comb 15)15% soluble insulin85% isophane insulin Biphasic human insulin (Insuman ® Comb 25)25% soluble insulin75% isophane insulin Biphasic human insulin (Insuman ® Comb 50)50% soluble insulin50% isophane insulin Analogue insulins Biphasic insulin lispro (Humalog ® Mix25)25% lispro75% lispro protamine Biphasic insulin lispro (Humalog ® Mix50)50% lispro50% lispro protamine Biphasic insulin aspart (NovoMix ® 30)30% aspart70% aspart protamine Higher proportion of rapid-acting insulin component provides greater activity in the postprandial period. UKHMG00596a February 2012

12. “Mid-mix” analogue insulins: Clinical data UKHMG00596a February 2012

13. Switching from twice-daily premixed insulin 30/70 or 25/75 to premixed insulin 50/50 Tanaka M, Ishii H (2010) J Int Med Res 38: 674–80 After switching to biphasic insulin lispro 50/50 *Participants were receiving biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine), biphasic human insulin 30/70 (30% rapid- acting insulin, 70% NPH), or biphasic insulin lispro 25/75 (25% lispro, 75% lispro protamine) AB=after breakfast; AL=after lunch; AS=after supper; BL=before lunch; BS=before supper; FBG=fasting blood glucose; NPH=neutral protamine Hagedorn. *P<0.05; **P<0.01. Before switching to biphasic insulin lispro 50/50* 12.5 10 7.5 5 2.5 0 –2.5 Change in blood glucose from FBG (mmol/L) FBG AB BL AL BS AS Bedtime ** * * n=13 Switching to twice- daily Mix 50/50 insulin injections controlled post-prandial blood glucose levels and stabilized diurnal blood glucose variations in patients with type 2 diabetes mellitus who had poor glucose control on insulin 70/30 or 75/25 UKHMG00596a February 2012

14. Cucinotta D et al (2009) Diabetes Obes Metab 11: 700–8 *Participants received twice-daily biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) throughout the study (ITT=200); **Participants received thrice-daily biphasic insulin aspart 50/50 (50% aspart, 50% aspart protamine) throughout the study (ITT=114), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=87); ***Participants received thrice-daily biphasic insulin aspart 70/30 (70% aspart, 30% aspart protamine) throughout the study (ITT=91), or switched their dinner insulin to biphasic insulin aspart 30/70 at 12 weeks (ITT=107). All regimens were in combination of metformin. NS=not significant; ITT=intent-to-treat. Comparison of thrice-daily biphasic insulin aspart 70/30, thrice-daily biphasic insulin aspart 50/50, and twice-daily biphasic insulin aspart 30/70 0 −0.5 −1 −1.5 −2 −0.30% (P=0.0004) NS Biphasic insulin aspart 30/70* 50/50 (30/70)** 70/30 (30/70)*** 8.9 7.3 8.8 7.2 8.9 7.0 Reduction in HbA 1c (%) Glycaemic control improved with thrice-daily biphasic insulin aspart 50/50 without higher incidence of hypoglycaemia compared with twice-daily insulin aspart 30/70 Reduction in mean HbA1c (%) at 36 weeks of treatment, intent-to-treat population UKHMG00596a February 2012

15. Thrice-daily biphasic insulin lispro 50/50 was non-inferior to basal–bolus therapy In people with type 2 diabetes uncontrolled on insulin glargine or lispro mix 25/75 (25% lispro, 75% lispro protamine): a non-inferiority intensification substudy of the DURABLE trial HbA 1c remained stable in both treatment groups Miser WF et al (2010) Clin Ther 32: 896–908 Biphasic insulin lispro 50/50 (n=174)Basal–bolus therapy* (n=171) HbA 1c (%) DURABLE=assessing durability of basal versus lispro mix 25/75 insulin efficacy. *Glargine plus mealtime insulin lispro. Baseline 9 8 7 6 5 4 3 2 1 3 6 0 Time (months) P=0.660 P=0.566 P=0.990 UKHMG00596a February 2012

16. Thrice-daily biphasic insulin aspart was non-inferior to basal–bolus therapy HbA 1c decreased from 9.1±0.7% to 7.8±1% in both treatment groups Ligthelm RJ et al (2006) Exp Clin Endocrinol Diabetes 114: 511–9 Biphasic insulin aspart* (n=196)Basal–bolus therapy** (n=198) HbA 1c (%) *BMI≤30 kg/m 2 : biphasic insulin aspart 70/30 (70% aspart, 30% aspart protamine) at breakfast and lunch and biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) at supper; BMI>30 kg/m 2 : biphasic insulin aspart 50/50 (50% aspart, 50% aspart protamine) at breakfast and lunch and biphasic insulin aspart 30/70 (30% aspart, 70% aspart protamine) at supper; **NPH plus mealtime aspart. BMI=body mass index; NPH=neutral protamine Hagedorn. 9 8 7 6 5 4 0 2 4 6 8 10 12 14 16 0 Time (week) 10 UKHMG00596a February 2012

17. Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Glycaemic control Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5 Participants were insulin-naïve people with type 2 diabetes who had suboptimal glycaemic control on maximal doses of oral antidiabetes drugs. Biphasic insulin lispro 50/50 (n=14) HbA 1c (%) 14 13 12 11 10 9 8 7 6 5 Basal–bolus therapy* (n=14) *NPH plus mealtime insulin lispro. NPH=neutral protamine Hagedorn. At entry 1 2 3 Time (months) 4 0 UKHMG00596a February 2012 Both the premix group and basal bolus group showed significant reduction in HbA1c over the 12 weeks

18. Twice-daily biphasic insulin lispro 50/50 vs. basal–bolus therapy: Insulin therapy-related quality of life questionnaire scores Score *NPH plus mealtime insulin lispro. **P≤0.05; ***P=NS. NPH=neutral protamine Hagedorn; NS=not significant. ** *** UKHMG00596a February 2012 Masuda H et al (2008) Diabetes Obes Metab 10: 1261–5 These results might suggest that twice-daily injections of premixed rapid-acting insulin analogue therapy could achieve good glycaemic control and better QOL compared with BB therapy in insulin-naıve type 2 diabetes.

19. Advantages of TDS “mid-mix” premixed insulins A thrice-daily “mid-mix” regimen comprehensively addresses the postprandial glucose peaks associated with the three main meals Compared with a basal–bolus regimen, a thrice- daily “mid-mix” regimen may be simpler to teach, and the single delivery device may benefit people who find it difficult to cope with the demands of frequent injections, glucose monitoring and necessary dose adjustments UKHMG00596a February 2012

20. Summary As people with type 2 diabetes get closer to HbA 1c targets, the significance of postprandial hyperglycaemia increases Biphasic insulin lispro 50/50 is an appropriate option to consider in a selected group of individuals UKHMG00596a February 2012

21. Practical factors to consider when changing a patient’s insulin regimen [insert name] UKHMG00596a February 2012

22. Key Factors LifestyleOccupation Diet & exercise Injection Frequency Self Monitoring of Blood Glucose Carbohydrate Awareness Dose Adjustment Motivation Language Barrier Cognitive ability Some practical factors to consider when changing a patient’s insulin regimen The factors that determine a patient’s regimen will be individual and vary from patient to patient UKHMG00596a February 2012

23. Basal–bolus therapy: How you might identify patients as uncontrolled Potential signs and clues to look for: – Erratic blood glucose control – Missing injections – Not adjusting doses – People who appear to not be engaged or who are frustrated UKHMG00596a February 2012

24. Potentially people who might fall into this category: – Those who are unable to dose adjust – Those who are not carbohydrate aware – Those who have problems with frequency of injections – Those who have problems grasping the concept of basal bolus Basal–bolus therapy: How you might identify patients as uncontrolled UKHMG00596a February 2012

25. How many of your patients with type 2 diabetes on a basal bolus regimen adjust their insulin based on the amount of carbohydrate they eat? UKHMG00596a February 2012

26. Premixed insulin Why might a premix offer an advantage? – Some people may find it a simpler regimen than basal–bolus therapy – Fewer injections – There can be less self-monitoring of blood glucose required – In some cases only one type of insulin and device is used – In some patients it can be less time consuming to teach than basal bolus UKHMG00596a February 2012

27. Premixed insulin Potentially people who are likely to benefit from this therapy: – Those who are unable or not wanting to adjust insulin doses / carbohydrate count – Those who prefer fewer injections UKHMG00596a February 2012

28. Premixed insulin Some of the perceived limitations: – In some patients it is a less flexible regimen – regular meals and a “structured” lifestyle required – There might be the potential to need to “feed” insulin – In some patients it might be more difficult to correct for high blood glucose levels UKHMG00596a January 2012

29. No panacea – need to discuss and tailor the insulin regimen to the individual UKHMG00596a February 2012